The long-term goal of this project is to develop quantitative imaging task based metrics and, using them, determine the fundamental limits on quantitative SPECT. In the previous project period, we focused on optimization of methods to correct for scatter, attenuation, and distance- dependent spatial resolution, as well as optimizing the acquisition strategy for imaging deep brain structures. In this renewal application, we turn our attention to the areas of simultaneous dual-isotope imaging, comparison of analytical and iterative image processing and reconstruction and on generalizing collimation advances, developed during the last project period for a dedicated brain system, to more commonly available dual-head systems. Our approaches include analysis, simulation, phantom experiments and patient studies. The analyses and simulation studies, although pertaining to prototypical estimation and classification tasks, will incorporate realistic anatomy and biological variability. We will continue the development of special-purpose collimators which sample the projections unequally in order to compensate for loss of information from central brain structures by attenuation. We will manufacture one such collimator, designed for a dedicated brain SPECT system during the last project period. We will design a similar collimator for a dual-head SPECT system, optimizing its performance for quantitative brain imaging tasks, relevant to Parkinson disease, using computer simulations of an anatomically realistic digital phantom. We will also determine the theoretical limits on activity estimation in simultaneous dual-energy imaging for both Tc/I and Tc/TI, and assess the value of dual-isotope imaging in clinical tasks related to glioblastoma and adult attention deficit hyperactivity disorder. We will compare analytical methods to correct for attenuation and distance dependent resolution to corrections incorporated into an iterative reconstruction algorithm in prototypical estimation tasks, as well as clinical tasks relevant to Alzheimer disease.